A novel paradigm of metabolic regulation: acute and chronic redox-circuitry control of energy homeostasis

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Skeletal muscle contraction requires an enormous amount of energy which is supplied mainly through carbohydrates and fats in our diet. Most of this energy is released in special organelles within muscle cells known as mitochondria which break down carbohydrates and fats through specific enzyme pathways. These enzymes must be activated rapidly during contraction. Traditional explanations for enzyme activation include the addition of high-energy molecules, such as phosphates (phosphorylation) to specific sites on enzymes (covalent regulation) or small compounds generated during contraction, such as metabolites, to other sites (allosteric regulation). However, there is evidence for a third form of regulating enzymes which has not been examined in detail with regards to skeletal muscle metabolism: redox signalling. ** Rather than changing enzyme activity through binding small molecules, redox signalling transfers energy from highly reactive chemicals known as oxidants. Many of these oxidants are produced during or after muscle contraction from multiple sources, including from blood vessels located near muscle cells, the cytoplasm within muscle cells themselves or possibly within the mitochondria, particularly after contraction, as a by-product of metabolism. These oxidants (such as superoxide, hydrogen peroxide, others) change the energy state of specific amino acids known as cysteines on enzymes. Cysteines are powerful regulators of proteins in other cell types and diseases (such as cancer) but have rarely been examined in skeletal muscle. Given that both contraction and diets produce oxidants, it is highly likely that redox-signalling is a powerful yet unexplained mechanism of regulating many metabolic pathways. This redox-paradigm may actually be a predominant method of regulating metabolism in muscle cells given that thousands of proteins contain exposed cysteines. This research proposal may provide a 'missing link' for understanding how diet and exercise regulate metabolism in skeletal muscle. This work will also train future researchers in advanced molecular, biochemical and physiological methods. ****